The Journal of Experimental Medicine
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Published 6 July 2004. doi:10.1084/jem.20040566
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 200, Number 1, 69-78
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15-epi-lipoxin A4–mediated Induction of Nitric Oxide Explains How Aspirin Inhibits Acute Inflammation

Mark J. Paul-Clark1, Thong van Cao1, Niloufar Moradi-Bidhendi2, Dianne Cooper1, and Derek W. Gilroy1

1 Department of Biochemical Pharmacology and 2 Department of Clinical Pharmacology, William Harvey Research Institute, St. Bartholomew's Hospital and The Royal London School of Medicine and Dentistry, London EC1M 6BQ, England, UK

Address correspondence to Derek W. Gilroy, Dept. of Biochemical Pharmacology, William Harvey Research Institute, St. Bartholomew's Hospital and The Royal London School of Medicine and Dentistry, Charterhouse Sq., London EC1M 6BQ, England, UK. Phone: 44-207-882-6069; Fax: 44-207-882-6076; email: d.w.gilroy{at}qmul.ac.uk

The established model for the mechanism of action of aspirin is the inhibition of prostaglandin synthesis. However, this has never fully explained aspirin's repertoire of antiinflammatory properties. We found in acute pleuritis that aspirin, but not salicylate, indomethacin, or piroxicam, increased plasma nitric oxide (NO), which correlated with a reduction in inflammation. Inhibiting aspirin-elicited NO pharmacologically in this model nullified the antiinflammatory effects of aspirin. Moreover, aspirin was not antiinflammatory in either constitutive (eNOS) or inducible NO synthase (iNOS) knockout mice with IL-1ß–induced peritonitis. It transpires that aspirin generates NO through its unique ability to trigger the synthesis of 15-epi-lipoxin A4. Aspirin and 15-epi-lipoxin A4 were shown to inhibit leukocyte trafficking in an NO-dependent manner using intravital microscopy on IL-1ß–stimulated mouse mesentery. Not only did aspirin inhibit leukocyte–endothelial interaction in a manner similar to NO in wild-type mice but both aspirin and 15-epi-lipoxin A4 had markedly reduced effects on leukocyte–endothelial cell adherence in eNOS- and iNOS-deficient mice compared with wild type. Collectively, these data suggest that aspirin triggers the synthesis of 15-epi-lipoxin A4, which increases NO synthesis through eNOS and iNOS. This aspirin-elicited NO exerts antiinflammatory effects in the microcirculation by inhibiting leukocyte–endothelium interactions.

Key Words: leukocyte trafficking • resolution • nonsteroidal antiinflammatory drugs • epi-lipoxins • microvascular endothelium

Abbreviations used in this paper: ANOVA, analysis of variance; COX, cyclooxygenase; eNOS, constitutive NO synthase; iNOS, inducible NO synthase; L-NAME, NG-nitro-L-arginine methyl ester; nNOS, neuronal NO synthase; NO, nitric oxide; NSAID, nonsteroidal antiinflammatory drug.


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